Assignment On " Process Of Durg Absorption From

Gastrointestinal Tract"
Drug Absorption
Drug absorption is determined by the drug’s physicochemical properties, formulation, and route of
administration. Dosage forms (eg, tablets, capsules, solutions), consisting of the drug plus other
ingredients, are formulated to be given by various routes (eg, oral, buccal, sublingual, rectal, parenteral,
topical, inhalational). Regardless of the route of administration, drugs must be in solution to be
absorbed. Thus, solid forms (eg, tablets) must be able to disintegrate and deaggregate.

A drug must cross several semipermeable cell membranes before it reaches the systemic circulation. Cell
membranes are biologic barriers that selectively inhibit passage of drug molecules. The membranes are
composed primarily of a bimolecular lipid matrix, which determines membrane permeability
characteristics. Drugs may cross cell membranes by

1. Passive diffusion
2. Active transport
3. Facilitated passive diffusion
4. Vasicular transport
5. Ion Pair absorption
6. Pore transport

Sometimes various globular proteins embedded in the matrix function as receptors and help transport
molecules across the membrane.

Passive diffusion
Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of low
concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the
molecule’s lipid solubility, size, degree of ionization, and the area of absorptive surface. Because the cell
membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small molecules tend to penetrate
membranes more rapidly than larger ones.

Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an aqueous
environment. The un-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell
membranes. The ionized form has low lipid solubility (but high water solubility—ie, hydrophilic) and high
electrical resistance and thus cannot penetrate cell membranes easily.
The proportion of the un-ionized form present (and thus the drug’s ability to cross a membrane) is
determined by the environmental pH and the drug’s pKa (acid dissociation constant). The pKa is the pH
at which concentrations of ionized and un-ionized forms are equal. When the pH is lower than the pKa,
the un-ionized form of a weak acid predominates, but the ionized form of a weak base predominates.
Thus, in plasma (pH 7.4), the ratio of un-ionized to ionized forms for a weak acid (eg, with a pKa of 4.4) is
1:1000; in gastric fluid (pH 1.4), the ratio is reversed (1000:1). Therefore, when a weak acid is given
orally, most of the drug in the stomach is un-ionized, favoring diffusion through the gastric mucosa. For
a weak base with a pKa of 4.4, the outcome is reversed; most of the drug in the stomach is ionized.

Theoretically, weakly acidic drugs (eg, aspirin) are more readily absorbed from an acid medium
(stomach) than are weakly basic drugs (eg, quinidine). However, whether a drug is acidic or basic, most
absorption occurs in the small intestine because the surface area is larger and membranes are more
permeable.

Active transport
In cellular biology, active transport is the movement of molecules across a cell membrane from a region
of lower concentration to a region of higher concentration—against the concentration gradient. Active
transport requires cellular energy to achieve this movement. There are two types of active transport:
primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that
uses an electrochemical gradient. An example of active transport in human physiology is the uptake of
glucose in the intestines.

Primary active transport

Primary active transport, also called direct active transport, directly uses metabolic energy to transport
molecules across a membrane.Substances that are transported across the cell membrane by primary
active transport include metal ions, such as Na+, K+, Mg2+, and Ca2+. These charged particles require
ion pumps or ion channels to cross membranes and distribute through the body.

Most of the enzymes that perform this type of transport are transmembrane ATPases. A primary ATPase
universal to all animal life is the sodium-potassium pump, which helps to maintain the cell potential. The
sodium-potassium pump maintains the membrane potential by moving three Na+ ions out of the cell for
every two K+ ions moved into the cell. Other sources of energy for primary active transport are redox
energy and photon energy (light). An example of primary active transport using redox energy is the
mitochondrial electron transport chain that uses the reduction energy of NADH to move protons across
the inner mitochondrial membrane against their concentration gradient. An example of primary active
transport using light energy are the proteins involved in photosynthesis that use the energy of photons
to create a proton gradient across the thylakoid membrane and also to create reduction power in the
form of NADPH.
Secondary active transport

In secondary active transport, also known as coupled transport or cotransport, energy is used to
transport molecules across a membrane; however, in contrast to primary active transport, there is no
direct coupling of ATP; instead it relies upon the electrochemical potential difference created by
pumping ions in/out of the cell. Permitting one ion or molecule to move down an electrochemical
gradient, but possibly against the concentration gradient where it is more concentrated to that where it
is less concentrated increases entropy and can serve as a source of energy for metabolism (e.g. in ATP
synthase). The energy derived from the pumping of protons across a cell membrane is frequently used
as the energy source in secondary active transport. In humans, sodium (Na+) is a commonly co-
transported ion across the plasma membrane, whose electrochemical gradient is then used to power
the active transport of a second ion or molecule against its gradient. In bacteria and small yeast cells, a
commonly cotransported ion is hydrogen. Hydrogen pumps are also used to create an electrochemical
gradient to carry out processes within cells such as in the electron transport chain, an important
function of cellular respiration that happens in the mitochondrion of the cell.

In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the sodium-
glucose cotransport as the mechanism for intestinal glucose absorption. Crane's discovery of
cotransport was the first ever proposal of flux coupling in biology.Cotransporters can be classified as
symporters and antiporters depending on whether the substances move in the same or opposite
directions.
Facilitated passive diffusion
Certain molecules with low lipid solubility (eg, glucose) penetrate membranes more rapidly than
expected. One theory is facilitated passive diffusion: A carrier molecule in the membrane combines
reversibly with the substrate molecule outside the cell membrane, and the carrier-substrate complex
diffuses rapidly across the membrane, releasing the substrate at the interior surface. In such cases, the
membrane transports only substrates with a relatively specific molecular configuration, and the
availability of carriers limits the process. The process does not require energy expenditure, and
transport against a concentration gradient cannot occur.

Facilitated diffusion is different from simple diffusion in several ways.

the transport relies on molecular binding between the cargo and the membrane-embedded channel or
carrier protein.

Itthe rate of facilitated diffusion is saturable with respect to the concentration difference between the
two phases; unlike free diffusion which is linear in the concentration difference.

The temperature dependence of facilitated transport is substantially different due to the presence of an
activated binding event, as compared to free diffusion where the dependence on temperature is mild.

Vesicular transport
A mechanism for transcellular transport in which a cell encloses extracellular material in an invagination
of the cell membrane to form a vesicle (endocytosis), then moves the vesicle across the cell to eject the
material through the opposite cell membrane by the reverse process (exocytosis). The transport
mechanism by which most proteins reach the Golgi apparatus or the plasma membrane; the vesicles
targeted toward lysosomes and secretory storage granules appear to be coated with clathrin.

Ion Pair Absorption

It is another mechanism is able to explain the absorption of such drugs which ionize at all pH condition.

· Transport of charged molecules due to the formation of a neutral complex with another charged
molecule carrying an opposite charge.

• Drugs have low c/w partition coefficient values, yet these penetrate the membrane by forming
reversible neutral complexes with endogenous ions.

e.g. mucin of GIT.

Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive
diffusion.

• This phenomenon is known as ion-pair transport.

Pore Transport
Also known as convective transport, bulk flow or filtration.

Important in the absorption of low mol. Wt. (less than 100). Low molecular size (smaller than the
diameter of the pore) & generally water-soluble drugs through narrow, aqueous filled channels or pores
in the membrane structure.

e.g. urea, water & sugars.

The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure difference
across the membrane.